Substituted benzamides, their production and their use as cysteine protease inhibitors

ABSTRACT

Benzamides of the formula I                    
     and its tautomeric forms, possible enantiomeric and diastereomeric forms, E and Z forms, and possible physiologically tolerated salts, in which the variables have the following meanings: 
     R 1 —C 1 -C 6 -alkyl, branched or unbranched, where one of the C atoms in this chain may be substituted by a phenyl ring, cyclohexyl ring, indolyl ring and an SCH 3  group, and the phenyl ring in turn is substituted by by [sic] a maximum of two R 4  radicals, where R 4  [lacuna] hydrogen, C 1 -C 4 -alkyl, branched or unbranched, —O—C 1 -C 4 -alkyl, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO—C 1 -C 4 -alkyl, NHCO—C 1 -C 4 -alkyl, and 
     R 2  can be NR 5 CO—R 6  and NHR 5 SO 2 —R 6 , and 
     R 3  is chlorine, bromine, fluorine, C 1 -C 6 -alkyl, NHCO—C 1 -C 4 -alkyl, NHSO 2 —C 1 -C 4 -alkyl, NO 2 , —O—C 1 -C 4 -alkyl, CN, COOH, CONH 2 , COO—C 1 -C 4 -alkyl, SO 2 —C 1 -C 4 -alkyl, —SO 2 Ph, SO 2 NH—C 1 -C 4 -alkyl, iodine, SO 2 NH 2  and NH 2 , and 
     A can be aromatic rings and heteroaromatic rings such as naphthyl, quinolyl, quinoxyl, benzimidazolyl, benzothienyl, quinazolyl, phenyl, thienyl, imidazolyl, pyridyl, pyrimidyl and pyridazyl, it also being possible for the rings to be substituted by by [sic] R 9  and up to 2 R 8  radicals, and 
     B a bond, —(CH 2 ) m —, —(CH 2 ) m —O—(CH 2 ) o —, —(CH 2 ) o —S—(CH 2 ) m —, —(CH 2 ) o —SO—(CH 2 ) m —, —(CH 2 ) o —SO 2 —(CH 2 ) m —, —CH═CH—, —C≡C—, —CO—CH═CH—, —(CH 2 ) o —CO—(CH 2 ) m —, —(CH 2 ) m —NHCO—(CH 2 ) o —, —(CH 2 ) m —CONH—(CH 2 ) o —, —(CH 2 ) m —NHSO 2 —(CH 2 ) o —, —NH—CO—CH═CH—, —(CH 2 ) m —SO 2 NH—(CH 2 ) o —, 
     A—B together also                    
     R 5  hydrogen and C 1 -C 4 -alkyl and 
     R 6  is hydrogen, phenyl, naphthyl, C 1 -C 6 -alkyl, linear or branched, it being possible for a C atom in the chain to be substituted by a phenyl ring which itself may also be substituted by one or two R 4  radicals, and 
     R 8  can be hydrogen, C 1 -C 4 -alkyl, branched or unbranched, —O—C 1 -C 4 -alkyl, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO—C 1 -C 4 -alkyl, —NHCO—C 1 -C 4 -alkyl, phenyl, NHCO-phenyl, —NHSO 2 —C 1 -C 4 -alkyl, —NHSO 2 -phenyl, —SO 2 —C 1 -C 4 -alkyl, pyridine [sic] and SO 2 -phenyl, 
     R 9  hydrogen, —CHR 14 —(CH 2 ) p —R 12  where R 12  pyrrolidine [sic], morpholine [sic], piperidine [sic], hexahydroazepine [sic], homopiperazine [sic],                    
      and R 10  [lacuna] C 1 -C 6 -alkyl, branched or unbranched, and which may also carry a phenyl ring which is in turn substituted by by [sic] a maximum of two R 11  radicals, where R 11  is hydrogen, C 1 -C 4 -alkyl, branched or unbranched, —O—C 1 -C 4 -alkyl, OH, Cl, F, Br, I, CF 3 , NO 2 , NH 2 , CN, COOH, COO—C 1 -C 4 -alkyl, NHCO—C 1 -C 4 -alkyl, —NHSO 2 —C 1 -C 4 -alkyl and —SO 2 —C 1 -C 4 -alkyl; and 
     R 13  is hydrogen and C 1 -C 6 -alkyl, branched or unbranched, and 
     n,p is [sic], independently of one another, a number 0, 1 or 2, and 
     m,o is [sic], independently of one another, a number 0, 1, 2, 3 or 4.

The present invention relates to novel benzamides which are inhibitorsof enzymes, especially cysteine proteases such as calpain (=calciumdependant cysteine proteases) and its isoenzymes and cathepsins, forexample B and L.

Calpains are intracellular proteolytic enzymes from the group ofcysteine proteases and are found in many cells. Calpains are activatedby an increase in the calcium concentration, a distinction being madebetween calpain I or μ-calpain, which is activated by μ-molarconcentrations of calcium ions, and calpain II or m-calpain, which isactivated by m-molar concentrations of calcium ions (P. Johnson, Int. J.Biochem. 1990, 22(8), 811-22). Further calpain isoenzymes have now beenpostulated too (K. Suzuki et al., Biol. Chem. Hoppe-Seyler, 1995,367(9), 523-9).

It is suspected that calpains play an important part in variousphysiological processes. These include cleavages of regulatory proteinssuch as protein kinase C, cytoskeletal proteins such as MAP 2 andspectrin, muscle proteins, protein degradation in rheumatoid arthritis,proteins in the activation of platelets, neuropeptide metabolism,proteins in mitosis and others which are listed in M. J. Barrett et al.,Life Sci. 1991, 48, 1659-69 and K. K. Wang et al., Trends in Pharmacol.Sci., 1994, 15, 412-9.

Elevated calpain levels have been measured in various pathophysiologicalprocesses, for example: ischemia of the heart (e.g. myocardial infarct),of the kidney or of the central nervous system (e.g. stroke),inflammations, muscular dystrophies, cataracts of the eyes, injuries tothe central nervous system (e.g. trauma), Alzheimer's disease etc. (seeK. K. Wang, above). It is suspected that there is a connection betweenthese disorders and elevated and persistent intracellular calciumlevels. This results in overactivation of calcium-dependent processes,which are then no longer subject to physiological control. Accordingly,overactivation of calpains may also induce pathophysiological processes.

It has therefore been postulated that inhibitors of calpain enzymes maybe useful for treating these disorders. Various investigations haveconfirmed this. Thus, Seung-Chyul Hong et al., Stroke 1994, 25(3), 663-9and R. T. Bartus et al., Neurological Res. 1995, 17, 249-58 have shown aneuroprotective effect of calpain inhibitors in acute neurodegenerativedisorders or ischemias like those occurring after stroke. Likewise,calpain inhibitors improved the recovery of the memory deficits andneuromotor disturbances occurring after experimental brain trauma (K. E.Saatman et al. Proc. Natl. Acad. Sci. USA, 1996, 93, 3428-3433). C. L.Edelstein et al., Proc. Natl. Acad. Sci. USA, 1995, 92, 7662-6, found aprotective effect of calpain inhibitors on kidneys damaged by hypoxia.Yoshida, Ken Ischi et al., Jap. Circ. J. 1995, 59(1), 40-8, were able toshow beneficial effects of calpain inhibitors after cardiac damageproduced by ischemia or reperfusion. Since the release of the β-AP4protein is inhibited by calpain inhibitors, a potential therapeutic usefor Alzheimer's disease has been proposed (J. Higaki et al., Neuron,1995, 14, 651-59). The release of interleukin-1α is likewise inhibitedby calpain inhibitors (N. Watanabe et al., Cytokine 1994, 6(6),597-601). It has further been found that calpain inhibitors havecytotoxic effects on tumor cells (E. Shiba et al. 20th Meeting Int. Ass.Breast Cancer Res., Sendai Jp, Sep. 25 to 28, 1994 Intl. J. Oncol. 5(Suppl.), 1994, 381). Further possible uses of calpain inhibitors aredetailed in K. K. Wang, Trends in Pharmacol. Sci., 1994, 15, 412-8.

Calpain inhibitors have already been described in the literature.However, these are mainly peptide inhibitors. Many known reversibleinhibitors of cysteine proteases such as calpain are, however, peptidealdehydes, in particular dipeptide and tripepide [sic] aldehydes suchas, for example, Z-Val-Phe-H (MDL 28170) (S. Mehdi, Trends in Biol. Sci.1991, 16, 150-3). Under physiological conditions, peptide aldehydes havethe disadvantage, owing to their great reactivity, that they are oftenunstable, may be rapidly metabolized and are prone to nonspecificreactions which may cause toxic effects (J. A. Fehrentz and B. Castro,Synthesis 1983, 676-78).

Peptide ketone derivatives are likewise inhibitors of cysteineproteases, in particular calpains. Thus, for example, ketone derivativeswhere the keto group is activated by an electron-attracting group suchas CF₃ are known to be inhibitors of serine proteases. In the case ofcysteine proteases, derivatives with ketones activated by CF₃ or similargroups have little or no activity (M. R. Angelastro et al., J. Med.Chem. 1990, 33, 11-13). To date only ketone derivatives in which, on theone hand, leaving groups in the a position cause irreversible inhibitionand, on the other hand, the keto group is activated by a carboxylic acidderivative have been found to be effective inhibitors of calpain (see M.R. Angelastro et al., see above; WO 92/11850; WO 92,12140; WO 94/00095and WO 95/00535). However, many of these inhibitors are derived frompeptides (Zhaozhao Li et al., J. Med. Chem. 1993, 36, 3472-80; S. L.Harbenson et al., J. Med. Chem. 1994, 37, 2918-29 and see above M. R.Angelastro et al.).

Ketone derivatives which have a hetero group in the α position have alsobeen described as calpain inhibitors. Thus, sulfur derivatives (see EP603873) and oxygen derivatives (see WO 95/15749 and R. E. Dolle et al.,J. Med. Chem. 1995, 38, 220-222) in which these hetero atoms are in theposition α to the ketone are known. Ketones which have an amino or amidogroup in the a position are likewise known, but usually in structuresderived from peptides. Thus, EP 603873 has mentioned α-amino radicalscarrying a heterocycle. α-Amides have likewise been described severaltimes: D. L. Flynn et al. J. Am. Chem. Soc. 1997, 119, 4874-4881; S.Natarajan et al., J. Enzym. Inhib. 1988, 2, 91-97; J. D. Godfrey et al.,J. Org. Chem. 1986, 51, 3073-3075; GB 2170200; EP 159156; EP 132304;U.S. Pat. No. 4,470,973 and JP 59033260. Most of the derivativesdescribed therein are substituted on the amide residue by other aminoacid derivatives. However, the amide

has likewise been described by D. L. Flynn et al. (see above). On theother hand, no derivatives in which the benzamide group has asubstituent are mentioned. In addition, most of the compounds have beenpostulated as inhibitors of angiotensin converting enzyme.

An analogous sulfonamide but once again without substitution on thebenzamide fragment has been described in R. F. Meyer et al., J. Med.Chem. 1982, 25, 996-996 [sic], also as inhibitor of angiotensinconverting enzyme. JP 06035142 (CA 121, 267626) has described benzamidederivatives analogous to the general structure I as photographicmaterial, although heterocycles such as hydantoins or other groupssensitive to oxidation reactions stand in R¹.

The novel compounds of the general formula I in which the substitutionson the benzamide and in the position α to the keto group play importantparts, with an amido or sulfonamido group being in the a position, havenot previously been described and are accordingly novel.

In a number of therapies, such as [lacuna] stroke, the activeingredients are administered intravenously, for example as infusionsolution. To do this it is necessary to have available substances, inthis case calpain inhibitors, which have adequate solubility in water sothat an infusion solution can be prepared. Many of the described calpaininhibitors have, however, the disadvantage that they have only low or nosolubility in water and thus are unsuitable for intravenousadministration. Active ingredients of this type can be administered onlywith ancillary substances intended to confer solubility in water (cf. R.T. Bartus et al. J. Cereb. Blood Flow Metab. 1994, 14, 537-544). Theseancillary substances, for example polyethylene glycol, often have sideeffects, however, or are even incompatible. A non-peptide calpaininhibitor which is soluble in water without ancillary substances wouldthus be a great advantage. Such inhibitors have scarcely been describedpreviously, and would thus show particular advantages.

Benzamide derivatives are described in the present invention. Thesecompounds are novel and a number of derivative surprisingly show thepossibility of obtaining potent non-peptide inhibitors of cysteineproteases, such as, for example, calpain, by incorporating rigidstructural fragments. In addition, all the present compounds of thegeneral formula I have at least one aliphatic amine radical and are thusable to bond [sic] salts with acids. This results in improved solubilityin water and thus the compounds show the required profile forintravenous administration as is necessary, for example, for stroketherapy.

The present invention relates to substituted benzamides of the generalformula I

and their tautomeric forms, possible enantiomeric and diastereomericforms, E and Z forms, and possible physiologically tolerated salts, inwhich the variables have the following meanings:

R¹—C₁-C₆-alkyl, branched or unbranched, where one of the C atoms in thischain may be substituted by a phenyl ring, cyclohexyl ring, indolyl ringand an SCH₃ group, and the phenyl ring in turn is substituted by by[sic] a maximum of two R⁴ radicals, where R⁴ hydrogen, C₁-C₄-alkyl,branched or unbranched, —O—C₁-C₄-alkyl, OH, Cl, F, Br, I, CF₃, NO₂, NH₂,CN, COOH, COO—C₁-C₄-alkyl, NHCO—C₁-C₄-alkyl, and

R² can be NR⁵CO—R⁶ and NHR⁵SO₂—R⁶, and

R³ is chlorine, bromine, fluorine, C₁-C₆-alkyl, NHCO—C₁-C₄-alkyl,NHSO₂—C₁-C₄-alkyl, NO₂, —O—C₁-C₄-alkyl, CN, COOH, CONH₂,COO—C₁-C₄-alkyl, SO₂—C₁-C₄-alkyl, —SO₂Ph, SO₂NH—C₁-C₄-alkyl, iodine,SO₂NH₂ and NH₂, and

A can be aromatic rings and heteroaromatic rings such as naphthyl,quinolinyl, quinoxalyl, benzimidazolyl, benzothienyl, quinazolyl,phenyl, thienyl, imidazolyl, pyridyl, pyrimidyl and pyridazyl, it alsobeing possible for the rings to be substituted by by [sic] R⁹ and up to2 R⁸ radicals, and

B is a bond, —(CH₂)_(m)—, —(CH₂)_(m)—O—(CH₂)_(o)—,—(CH₂)_(o)—S—(CH₂)_(m)—, —(CH₂)O—SO—(CH₂)_(m)—,—(CH₂)_(o)—SO₂—(CH₂)_(m)—, —CH═CH—, —C≡C—, —CO—CH═CH—,—(CH₂)_(o)—CO—(CH₂)_(m)—, —(CH₂)_(m)—NHCO—(CH₂)_(o)—,—(CH₂)_(m)—CONH—(CH₂)_(o)—, —(CH₂)_(m)—NHSO₂—(CH₂)_(o)—, —NH—CO—CH═CH—,—(CH₂)m—SO₂NH—(CH₂)_(o)—,

A—B together also

R⁵ hydrogen and C₁-C₄-alkyl and

R⁶ is hydrogen, phenyl, naphthyl, C₁-C₆-alkyl, linear or branched, itbeing possible for a C atom in the chain to be substituted by a phenylring which itself may also be substituted by one or two R⁴ radicals, and

R⁸ can be hydrogen, C₁-C₄-alkyl, branched or unbranched, —O—C₁-C₄-alkyl,OH, Cl, F, Br, I, CF₃, NO₂, NH₂, CN, COOH, COO—C₁-C₄-alkyl,—NHCO—C₁-C₄-alkyl, phenyl, NHCO-phenyl, —NHSO₂—C₁-C₄-alkyl,—NHSO₂-phenyl, —SO₂—C₁-C₄-alkyl, pyridine [sic] and SO₂-phenyl,

R⁹ hydrogen, —CHR¹⁴—(CH₂)_(p)—R¹² where R¹² pyrrolidine [sic],morpholine [sic], piperidine [sic], hexahydroazepine [sic],homopiperazine [sic],

 and R¹⁰ [lacuna] C₁-C₆-alkyl, branched or unbranched, and which mayalso carry a phenyl ring which is in turn substituted by by [sic] amaximum of two R¹¹ radicals, where R¹¹ is hydrogen, C₁-C₄-alkyl,branched or unbranched, —O—C₁-C₄-alkyl, OH, Cl, F, Br, I, CF₃, NO₂, NH₂,CN, COOH, COO—C₁-C₄-alkyl, NHCO—C₁-C₄-alkyl, —NHSO₂—C₁-C₄-alkyl and—SO₂—C₁-C₄-alkyl; and

R¹³ is hydrogen and C₁-C₆-alkyl, branched or unbranched, and

n,p is [sic], independently of one another, a number 0, 1 or 2, and

m,o is [sic], independently of one another, a number 0, 1, 2, 3 or 4.

Preferred compounds of the general formula I are those in which

A is phenyl and naphthyl, each of which may be substituted by R⁹, and

B is —SO₂NH—, —CH═CH—, a bond, and —C≡C— and

R¹ ethyl, propyl, butyl and benzyl,

R² is NH—SO₂—R⁶ and NH—CO—R⁶ and

R³ is hydrogen and COOR and

R⁶ is C₁-C₄-alkyl, branched and unbranched, and phenyl and

R⁹ hydrogen, —(CH₂)—R¹² where R¹² pyrrolidine [sic], morpholine [sic],piperidine [sic],

 and R¹⁰ C₁-C₆-alkyl, branched or unbranched, and

R¹³ can be C₁-C₄-alkyl, branched or unbranched.

Particularly preferred compounds of the general formula I are those inwhich

A is phenyl which may also be substituted by R⁹, and

B is —CH═CH—, and the B radical is in the ortho position to [sic] thebenzamide of the general formula I, and

R¹ butyl and benzyl

R² is NH—SO₂—R⁶ and

R³ is hydrogen and

R⁶ is C₁-C₄-alkyl, branched and unbranched, and phenyl and

R⁹ hydrogen, —(CH₂)—R¹² where R¹² pyrrolidine [sic], morpholine [sic],piperidine [sic],

 and R¹⁰ C₁-C₆-alkyl, branched or unbranched, and

R¹³ C₁-C₄-alkyl, branched or unbranched,

R¹⁴ can be hydrogen, methyl, ethyl.

The compounds of the formula I can be employed as racemates, asenantiomerically pure compounds or as diastereomers. If enantiomericallypure compounds are required, these can be obtained, for example, bycarrying out a classical racemate resolution with the compounds of theformula I or their intermediates using a suitable optically active baseor acid. On the other hand, the enantiomeric compounds can likewise beprepared by using commercially purchasable compounds, for exampleoptically active amino acids such as phenylalanine, tryptophan andtyrosine.

The invention also relates to compounds which are mesomers or tautomersof compounds of the formula I, for example those in which the keto groupin formula I is in the form of an enol tautomer.

The invention further relates to the physiologically tolerated salts ofthe compounds I which can be obtained by reacting compounds I with asuitable acid or base. Suitable acids and bases are listed, for example,in Fortschritte der Arzneimittelforschung, 1966, Birkhäuser Verlag, Vol.10, pp. 224-285. These include, for example, hydrochloric acid, citricacid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid,acetic acid, formic acid, maleic acid, fumaric acid etc., and sodiumhydroxide, lithium hydroxide, potassium hydroxide and tris.

The novel compounds of the general formula I can be prepared in variousways as described hereinafter (see scheme 1).

A benzoic acid II, which, where appropriate, [lacuna] simply fromanalogous esters by hydrolysis with acids such as hydrochloric acid, orbases such as lithium hydroxide or sodium hydroxide, in aqueoussolutions or water/solvent mixtures, such as water/alcohols orwater/tetrahydrofuran, at room temperature or elevated temperature, upto the boiling point of the solvent, are [sic] reacted with appropriateamino alcohols III to give the benzamides IV. This entails use ofconventional peptide coupling methods which are detailed either in C. R.[sic] Larock, Comprehensive Organic Transformations, VCH Publisher,1989, page 972 et seq., or in Houben-Weyl, Methoden der organischenChemie, 4th edition, E5, Chapter V. It is preferred to use “activated”acid derivatives of II, with the acid group COOH being converted into aCOL group. L is a leaving group such as, for example, C1, imidazole andN-hydroxybenzotriazole. This activated acid is subsequently reacted withamines to give the amides IV. The reaction takes place in anhydrousinert solvents such as methylene chloride, tetrahydrofuran anddimethylformamide at temperatures from −20 to +40° C.

The amino alcohols III are prepared from analogous alcohols VII (forgeneral method of synthesis, see: J. C. Barrish et al., J. Med. Chem.1994, 37, 1758-1768). This entailed reacting VII, analogous to theabove, with acids or sulfonic acids to give the corresponding amides orsulfonamides VIII. The protective group Z, which is usually BOC or Cbz,are [sic] then eliminated. This entails the use of conventionalprocedures, for example with BOC acids such as trifluoroacetic acid orhydrochloric acid, in solvents such as methylene chloride or mixtures ofwater and alcohols or tetrahydrofuran.

The alcohol derivatives IV can be oxidized to the novel aldehyde [sic]derivatives I. It is possible to use for this various conventionaloxidation reactions (see C. R. [sic] Larock, Comprenhensive [sic]Organic Transformations, VCH Publisher, 1989, page 604 et seq.) such as,for example, Swern and Swern-analogous oxidations (T. T. Tidwell,Synthesis, 1990, 857-70), sodium hypochloride [sic]/TEMPO (S. L.Harbenson et al., see above) or Dess-Martin (J. Org. Chem. 1983, 48,4155). These are preferably carried out in inert aprotic solvents suchas dimethylformamide, tetrahydrofuran or methylene chloride withoxidizing agents such as DMSO/pyridine×SO₃, DMSO/oxalyl chloride orDMSO/DCC or EDC at temperatures from −50 to +25° C., depending on themethod (see the above literature).

Alternatively, an amino alcohol III can be reacted with a benzoic acid Vin analogy to the linkage of II and III to give the benzamide derivativeVI. In this case, R′ is a functional group which then permits conversioninto the AB radicals according to the invention (see below). Thus, R′ inVI can be, for example, a nitro group which can subsequently be reducedcatalytically in conventional ways, for example with palladium/carbon inwater-soluble solvents such as alcohols, with hydrogen to give ananalogous aniline (R′═NH₂). This amino group can then be converted intoamides or sulfonamides. This entails the aniline being reacted withcarboxylic acid or sulfonic acid derivatives in analogy to the (II+III)linkage.

Further radicals and transformation thereof can be respectively employedand carried out in analogy to the methods mentioned for preparing theAB-substituted benzoic acid derivatives.

In the cases where R³ in IV is a carboxylic ester, this can behydrolyzed with bases and acids, for example lithium hydroxide, sodiumhydroxide and hydrochloric acid, in aqueous systems or water/solventmixtures, such as water/alcohols and water/tetrahydrofuran, to thecarboxylic acid, either at room temperature or at elevated temperature(up to the boiling point of the solvent). The oxidation to I is thencarried out as described above.

Synthesis of the carboxylic esters II have [sic] already been describedin some cases, or can be prepared [sic] by conventional chemicalmethods.

Compounds in which B is a bond are prepared by conventional aromaticcoupling, for example Suzuki coupling with boric acid derivatives andhalides with palladium catalysis, or copper-catalyzed coupling ofaromatic halides. The alkyl-bridged radicals (B=—(CH₂)_(m)—) can beprepared by reducing the analogous ketones or by alkylating theorganolithium, e.g. ortho-phenyloxazolidines [sic], or otherorganometallic compounds (cf. I. M. Dordor et al., J. Chem. Soc. PerkinTrans. I, 1984, 1247-52).

Ether-bridged derivatives are prepared by alkylating the correspondingalcohols or phenols with halides. The sulfoxides and sulfones can beobtained by oxidizing the corresponding thioethers. Alkene- andalkyne-bridged compounds are prepared, for example, by the Heck reactionfrom aromatic halides and appropriate alkenes and alkynes (cf. I.Sakamoto et al., Chem. Pharm. Bull., 1986, 34, 2754-59). The chalkonesare produced by condensing acetophenones with aldehydes and can, whereappropriate, be converted into the analogous alkyl derivatives byhydrogenation. Amides and sulfonamides are prepared from the amines andacid derivatives in analogy to the methods described above.

The benzamide derivatives I of the present invention are inhibitors ofcysteine proteases, especially cysteine proteases such as calpains I andII and cathepsins B and L.

The inhibitory effect of the benzamides I has been determined usingenzyme assays known from the literature, determining as criterion ofeffect a concentration of the inhibitor at which 50% of the enzymeactivity is inhibited (=IC₅₀). The amides I were measured in this wayfor their inhibitory effect on calpain I, calpain II and cathepsin B.

Cathepsin B Assay

The inhibition of cathepsin B was determined by a method analogous tothat of S. Hasnain et al., J. Biol. Chem., 1993, 268, 235-40. 2 μl of aninhibitor solution prepared from inhibitor and DMSO (finalconcentrations: 100 μM to 0.01 μM) are added to 88 μL of cathepsin B(cathepsin B from human liver (Calbiochem), diluted to 5 units in 500 μMbuffer). This mixture is preincubated at room temperature (25° C.) for60 minutes and then the reaction is started by adding 10 μl of 10 mMZ-Arg-Arg-pNA (in buffer with 10% DMSO). The reaction is followed in amicrotiter plate reader at 405 nM [sic] for 30 minutes. The IC₅₀s arethen determined from the maximum gradients.

Calpain I and II Assay

The testing of the inhibitory properties of calpain inhibitors takesplace in buffer with 50 mM tris-HCl, pH 7.5; 0.1 M NaCl; 1 mMdithiotreithol [sic]; 0.11 mM CaCl₂, using the fluorogenic calpainsubstrate Suc-Leu-Tyr-AMC (25 mM dissolved in DMSO, Bachem/switzerland).Human μ-calpain is isolated from erythrocytes, and enzyme with apurity >95%, assessed by SDS-PAGE, Western blot analysis and N-terminalsequencing, is obtained after more [sic] chromatographic steps(DEAE-Sepharose, phenyl-Sepharose, Superdex 200 and blue Sepharose). Thefluorescence of the cleavage product 7-amino-4-methylcoumarin (AMC) isfollowed in a Spex Fluorolog fluorimeter at λex=380 nm and λem =460 nm.The cleavage of the substrate is linear in a measurement range of 60min., and the autocatalytic activity of calpain is low, if the tests arecarried out at temperatures of 12° C. The inhibitors and the calpainsubstrate are added to the test mixture as DMSO solutions, and the finalconcentration of DMSO ought not to exceed 2%.

In a test mixture, 10 μl of substrate (250 μM final) and then 10 μl ofμ-calpain (2 μg/ml final, i.e. 18 nM) are added to a 1 ml cuvettecontaining buffer. The calpain-mediated cleavage of the substrate ismeasured for from 15 to 20 min. Then 10 μl of inhibitor (from 50 to 100μM solution in DMSO) are added and the inhibition of cleavage ismeasured for a further 40 min. K_(i) values are determined using theclassical equation for reversible inhibition:

Ki=I(v₀/v_(i))−1;

where I=inhibitor concentration,

v₀=initial rate before addition of the inhibitor;

v_(i)=reaction rate at equilibrium.

The rate is calculated from v=AMC liberation/time, i.e. height/time.

On testing3(2-naphthylsulfonamido)-N(3(S)-4-phenyl-1-phenylsulfonamidobutan-2-on-3-yl)benzamide[sic] (Example 1), an inhibition of more than 50% of calpain I was foundat a concentration of 1 μM, and thus the K_(i) for Example 1 is <1 μM.

Calpain is an intracellular cysteine protease. Calpain inhibitors mustpass through the cell membrane in order to prevent intracellularproteins being broken down by calpain. Some known calpain inhibitors,such as, for example, E 64 and leupeptin, cross cell membranes onlypoorly and accordingly show only a poor effect on cells, although theyare good calpain inhibitors. The aim is to find compounds better able tocross membranes. Human platelets are used to demonstrate the ability ofcalpain inhibitors to cross membranes.

Calpain-mediated breakdown of tyrosine kinase pp60src in platelets

Tyrosine kinase pp60src is cleaved by calpain after activation ofplatelets. This has been investigated in detail by Oda et al. in J.Biol. Chem., 1993, 268, 12603-12608. This revealed that the cleavage ofpp60src can be prevented by calpeptin, a calpain inhibitor. The cellularefficacy of our substances was tested based on this publication. Fresh,citrated, human blood was centrifuged at 200 g for 15 min. Theplatelet-rich plasma was pooled and diluted 1:1 with platelet buffer(platelet buffer: 68 mM NaCl, 2.7 mM KCl, 0.5 mM MgCl₂×6 H₂O, 0.24 mMNaH₂PO₄×H₂O, 12 mM NaHCO₃, 5.6 mM glucose, 1 mM EDTA, pH 7.4). After acentrifugation step and washing step with platelet buffer, the plateletswere adjusted to 10⁷ cells/ml. The human platelets were isolated at RT.

In the assay mixture, isolated platelets (2×10⁶) were preincubated withvarious concentrations of inhibitors (dissolved in DMSO) at 37° C. for 5min. The platelets were then activated with 1 μM ionophore A23187 and 5mM CaCl₂. After incubation for 5 min., the platelets were brieflycentrifuged at 13000 rpm, and the pellet was taken up in SDS samplebuffer (SDS sample buffer: 20 mM Tris-HCl, 5 mM EDTA, 5 mM EGTA, 1 mMDTT, 0.5 mM PMSF, 5 μg/ml leupeptin, 10 μg/ml pepstatin, 10% glyceroland 1% SDS). The proteins were fractionated in a 12% gel, and pp60srcand its 52 kDa and 47 kDa cleavage products were identified by Westernblotting. The polyclonal rabbit antibody used, anti-Cys-src(pp60^(c-rc)), was purchased from Biomol Feinchemikalien (Hamburg). Thisprimary antibody was detected using a second, HRP-coupled goat antibody(Boehringer Mannheim, FRG). The Western blotting was carried out byknown methods.

The cleavage of pp60src was quantified by densitometry, using ascontrols unactivated (control 1: no cleavage) and ionophore- andcalcium-treated platelets (control 2: corresponds to 100% cleavage). TheED₅₀ corresponds to the concentration of inhibitor at which theintensity of the color reaction is reduced by 50%.

Glutamate-induced Cell Death in Cortical Neurones

The test was carried out as in Choi D. W., Maulucci-Gedde M. A. andKriegstein A. R., “Glutamate neurotoxicity in cortical cell culture”. J.Neurosci. 1989 [sic], 7, 357-368. The cortex halves were dissected outof 15-day old mouse embryos and the single cells were obtainedenzymatically (trypsin). These cells (glia and cortical neurones) areseeded out in 24-well plates. After three days (laminin-coated plates)or seven days (ornithine-coated plates), the mitosis treatment iscarried out with FDU (5-fluoro-2-deoxyuridines [sic]). 15 days afterpreparation of the cells, cell death is induced by adding glutamate (15minutes). After removal of glutamate, the calpain inhibitors are added.24 hours later, the cell damage is estimated by determining lactatedehydrogenase (LDH) in the cell culture supernatant.

It is postulated that calpain is also involved in programmed cell death(M. K. T. Squier et al., J. Cell. Physiol. 1994, 159, 229-237; T. Patelet al. Faseb Journal 1996, 590, 587-597). For this reason, in anothermodel, cell death was induced in a human cell line with calcium in thepresence of a calcium ionophore. Calpain inhibitors must get inside thecell and inhibit calpain there in order to prevent the induced celldeath.

Calcium-mediated Cell Death in NT2 Cells

Cell death can be induced in the human cell line NT2 by calcium in thepresence of the ionophore A 23187. 10⁵ cells/well were plated out inmicrotiter plates 20 hours before the test. After this period, the cellswere incubated with various concentrations of inhibitors in the presenceof 2.5 μM ionophore and 5 mM calcium. 0.05 ml of XTT (Cell ProliferationKit II, Boehringer Mannheim) was added to the reaction mixture after 5hours. The optical density was determined approximately 17 hours later,in accordance with the manufacturer's information, in an SLT Easy ReaderEAR 400. The optical density at which half the cells have died iscalculated from the two controls with cells without inhibitors incubatedin the absence and presence of ionophore.

Elevated glutamate activities occur in a number of neurologicaldisorders or psychological disturbances and lead to states ofoverexcitation or toxic effects in the central nervous system (CNS). Theeffects of glutamate are mediated by various receptors. Two of thesereceptors are classified, in accordance with the specific agonists, asNMDA receptor and AMPA receptor. Antagonists to these glutamate-mediatedeffects can thus be employed for treating these disorders, in particularfor therapeutic use for neurodegenerative disorders such as Huntington'schorea and Parkinson's disease, neurotoxic impairments after hypoxia,anoxia, ischemia and after lesions like those occurring after stroke andtrauma, or else as antiepileptics (cf. Arzneim. Forschung 1990, 40,511-514; TIPS, 1990, 11, 334-338; Drugs of the Future 1989, 14,1059-1071).

Protection from Cerebral Overexcitation by Excitatory Amino Acids (NMDAand AMPA Antagonism in Mice)

Intracerebral administration of excitatory amino acids (EAA) inducessuch drastic overexcitation that it leads to convulsions and death ofthe animals (mice) within a short time. These signs can be inhibited bysystemic, e.g. intraperitoneal, administration of centrally actingsubstances (EAA antagonists). Since excessive activation of EAAreceptors in the central nervous system plays a significant part in thepathogenesis of various neurological disorders, it is possible to inferfrom the detected EAA antagonism in vivo that the substances may havetherapeutic uses for such CNS disorders. As a measure of the efficacy ofthe substances, an ED₅₀ was determined, at which 50% of the animals arefree of signs, owing to the previous i.p. administration of the testsubstance, by means of a fixed dose of either NMDA or AMPA.

The benzamide derivatives I are inhibitors of cysteine derivatives [sic]like calpain I and II and cathepsin B and L, and can thus be used tocontrol diseases associated with an elevated activity of calpain enzymesor cathepsin enzymes. The present amides I can accordingly be used totreat neurodegenerative disorders occurring after ischemia, trauma,subarachnoid hemorrhages and stroke, and neurodegenerative disorderssuch as multi-infarct dementia, Alzheimer's disease, Huntington'sdisease and epilepsies and, in addition, to treat damage to the heartafter cardiac ischemia and damage due to reperfusion after vascularocclusions, damage to the kidneys after renal ischemia, skeletal muscledamage, muscular dystrophies, damage arising through proliferation ofsmooth muscle cells, coronary vasospasms, cerebral vasospasms, cataractsof the eyes, restenosis of the blood vessels after angioplasty. Inaddition, the amides I may be useful in the chemotherapy of tumors andmetastasis thereof and for treating diseases in which an elevatedinterleukin-1 level occurs, such as inflammations and rheumaticdisorders.

The pharmaceutical preparations according to the invention comprise atherapeutically effective amount of the compounds I in addition toconventional pharmaceutical ancillary substances. The active ingredientscan be present in the usual concentrations for local external use, forexample in dusting powders, ointments or sprays. As a rule, the activeingredients are present in an amount of from 0.001 to 1% by weight,preferably 0.001 to 0.1% by weight.

For internal use, the preparations are administered in single doses.From 0.1 to 100 mg are given per kg of body weight in a single dose. Thepreparation may be administered in one or more doses each day, dependingon the nature and severity of the disorders.

The pharmaceutical preparations according to the invention comprise,apart from the active ingredient, the customary excipients and diluentsappropriate for the required mode of administration. For local externaluse it is possible to use pharmaceutical ancillary substances such asethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenatedcastor oil, polyacrylic acid, polyethylene glycol, polyethylene glyco[sic] stearate, ethoxylated fatty alcohols, liquid paraffin, petrolatumand wool fat. Suitable examples for internal use are lactose, propyleneglycol, ethanol, starch, talc and polyvinylpyrrolidone.

It is also possible for antioxidants such as tocopherol and butylatedhydroxyanisole, and butylated hydroxytoluene, flavor-improvingadditives, stabilizers, emulsifiers and lubricants to be present.

The substances which are present in the preparation in addition to theactive ingredient, and the substances used in producing thepharmaceutical preparations, are toxicologically acceptable andcompatible with the active ingredient in each case. The pharmaceuticalpreparations are produced in a conventional way, for example by mixingthe active ingredient with other [sic] customary excipients anddiluents.

The pharmaceutical preparations can be administered in various ways, forexample orally, parenterally, such as intravenously by infusion,subcutaneously, intraperitoneally and topically. Thus, possiblepresentations are tablets, emulsions, solutions for infusion andinjection, pastes, ointments, gels, creams, lotions, dusting powders andsprays.

EXAMPLES Example 13(2-Naphthylsulfonamido)-N(3(S)-4-phenyl-1-phenylsulfonamidobutan-2-on-3-yl)benzamide[sic]

a) O-tert-Butyl N(1-nitro-4-phenylbutan-2-ol-3-yl)carbamate [sic]

31.8 g (0.52 mol) of nitromethane and 12.5 ml of diethylamine weredissolved in 125 ml of ethanol. Then 43.3 g (0.17 mol) of O-tert-butylN(2(S)-3-phenylpropion-1-al-3-yl)carbamate [sic] (A. W. Konradi et al.,J. Am. Chem. Soc. 1994, 1316-1323) were added in portions. The reactionmixture was then stirred at room temperature for 16 h. The mixture wassubsequently concentrated in vacuo. The residue was dissolved in ethylacetate and washed successively with 5% strength aqueous citric acid andaqueous sodium bicarbonate solutions. The organic phase was dried andconcentrated in vacuo, resulting in 51.4 g (95%) of the product.

b)N(2(R,S)-3(S)-1-Ammonium-4-phenylbutan-2-ol-3-yl)-O-tert-butylcarbamateAcetate [sic]

58.9 g (0.19 mol) of intermediate 1a were dissolved in 750 ml oftetrahydrofuran/methanol (2/1) and, after addition of 58 g ofpalladium/barium sulfate (5%) and 10 ml of glacial acetic acid, reducedwith hydrogen. The mixture was then filtered and the filtrate wasconcentrated in vacuo. The residue was treated with ether, whereupon theproduct crystallized out as acetate.

c) O(tert-Butyl)N(2(R,S)-3(S)-1-phenylsulfonamido-4-phenylbutan-2-ol-3-yl)carbamate[sic]

2.5 g (7.3 mmol) of intermediate 1b were dissolved in 25 ml of pyridine.Then, at 0° C., 1.36 g (7.7 mmol) of benzenesulfonyl chloride, dissolvedin 5 ml of anhydrous tetrahydrofuran, were rapidly added dropwise. Thereaction mixture was then stirred at room temperature for 16 h. Thereaction mixture was concentrated in vacuo, and the resulting residuewas treated with water, whereupon the product slowly crystallized out.2.6 g (89%) of the product were obtained.

d) N(2(R,S)-3(S)-3-Amino-4-phenylbutan-2-ol-1-yl)benzenesulfonamide[sic]

2.2 g (5.1 mmol) of intermediate 1c were dissolved in 50 ml of methylenechloride, and 50 ml of saturated ethereal hydrogen chloride solutionwere added. The mixture was stirred at room temperature for 1 h. Thereaction mixture was then concentrated in vacuo, and the resultingresidue was treated with ether, whereupon the product slowly separatedout as hydrochloride. Yield 1.8 g (97%).

e) Ethyl 3(2-naphthylsulfonamido)benzoate

34.3 g (0.15 mol) of 2-naphthalenesulfonyl chloride, dissolved in 250 mlof tetrahydrofuran, were added dropwise to 25 g (0.15 mol) of ethyl3-aminobenzoate and 63 ml (0.45 mol) of triethylamine in 400 ml oftetrahydrofuran at 0° C. The mixture was then heated to reflux for 1 h.The organic solvent was removed in vacuo, and the residue waspartitioned between ethyl acetate and water. The ethyl acetate phase wasdried and concentrated in vacuo. 55 g (100%) of the product wereobtained.

f) 3(2-Naphthylsulfonamido)benzoic Acid

55 g (0.15 mol) of intermediate 7a were dissolved in 400 ml oftetrahydrofuran, and 400 ml of 4M sodium hydroxide solution were added.The mixture was stirred at 60° C. for 1.5 h. The organic solvent wasremoved in vacuo. The remaining aqueous phase was stirred into dilutehydrochloric acid. The resulting precipitate was dissolved in ethylacetate, washed with water, dried and concentrated in vacuo. The residuewas then treated with methylene chloride. 37.3 g (75%) of the productwere subsequently obtained.

g)3(2-Naphthylsulfonamido)-N(2(R,S)-3(S)-4-phenyl-1-phenylsulfonamidobutan-2-ol-3-yl)benzamide[sic]

0.87 g (2.7 mmol) of intermediate 1f and 0.36 g (2.7 mmol) of1-hydroxybenzotriazole were dissolved in 5 ml of anhydrous dimethylsulfoxide. Then a further solution of 0.95 g (2.7 mmol) of intermediate1d and 0.94 g (9.3 mmol) of triethylamine in 5 ml of anhydrous dimethylsulfoxide was prepared and added to the first solution. 0.56 g (2.9mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloridewas then given added [sic], and the mixture was stirred at roomtemperature for 16 h. The reaction mixture was then mixed with about 100ml of an aqueous sodium chloride/sodium bicarbonate solution, whereuponthe product was noticeable.

Yield: 0.54 g (88%).

h)3(2-Naphthylsulfonamido)-N(3(S)-4-phenyl-1-phenylsulfonamidobutan-2-on-3-yl)benzamide[sic]

0.2 g (0.32 mmol) of intermediate 1g and 0.16 g (1.6 mmol) oftriethylamine were dissolved in 5 ml of anhydrous dimethyl sulfoxide.Then, at room temperature, 0.2 g (1.3 mmol) of pyridine/sulfur trioxidecomplex was added and the mixture was stirred for 16 h. The reactionmixture was poured into 50 ml of an aqueous sodium chloride/sodiumbicarbonate solution, whereupon the product separated out. Yield 0.16 g(80%).

¹H-NMR (D₆-DMSO): δ=2.8 (1H), 3.1 (1H), 3.8 (1H), 4.0 (1H), 4.6 (1H),7.0-8.2 (21H), 8.4 (1H), 8.8 (1H) and 10.6 (broad) ppm.

Example 2N(3(S)-4-Phenyl-1-phenylsulfonamidobutan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)benzamide[sic]

a) Ethyl 2(E-2(4-pyridyl)-1-ethenyl)benzoate

50 g (0.22 mol) of ethyl 2-bromobenzoate, 30 g (0.29 mol) of4-vinylpyridine and 75 ml (0.54 mol) of triethylamine were dissolved in750 ml of dimethylformamide. Then 0.36 g of palladium(II) acetate, 0.96g of tri(o-tolyl)phosphine and 1 ml of water were added and the mixturewas refluxed for 3 h. The reaction mixture was then poured intoice-water and extracted with ethyl acetate. The organic phase was driedand concentrated in vacuo. The residue was recrystallized [lacuna]cyclohexane/petroleum ether, resulting in 45.3 g (83%) of the product.

b) 2(E-2(4-Pyridyl)-1-ethenyl)benzoic Acid

45 g (0.18 mol) of intermediate 2a were dissolved in 200 ml oftetrahydrofuran and, after 400 ml of 4M sodium hydroxide solution hadbeen added, the mixture was refluxed for 4 h. After cooling, the mixturewas diluted with 600 ml of water and neutralized with acetic acid,whereupon the product crystallized out. Yield 38.2 g (95%).

c)N(2(R,S)-3(S)-4-Phenyl-1-phenylsulfonamidobutan-2-ol-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)benzamide[sic]

0.75 g (2.1 mmol) of intermediates [sic] 1d and 0.47 g (2.1 mmol) ofintermediate 2b were reacted in analogy to method 1g, resulting in 0.97g (87%) of the product.

d)N(3(S)-4-Phenyl-1-phenylsulfonamidobutan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)benzamide[sic]

0.87 g of intermediate 2c were oxidized in analogy to method 1h,resulting in 0.78 g of the product.

¹H-NMR (D₆-DMSO): δ=2.8 (1H), 3.1 (1H), 3.9 (1H), 4.1 (1H), 4.8 (1H),7.0-8.2 (18H), 8.6 (2H) and 8.9 (1H) ppm.

Example 3N(3(S)-1-Methanesulfonamido-4-phenylbutan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)benzamide[sic]

a) O(tert-Butyl)N(2(R,S)-3(S)-1-methanesulfonamido-4-phenylbutan-2-ol-3-yl)carbamate[sic]

2.5 g (7.3 mmol) of intermediate 1b were dissolved in 25 ml of pyridine.Then, at 0° C., 0.88 g (7.7 mmol) of methanesulfonyl chloride, dissolvedin 5 ml of anhydrous tetrahydrofuran, was rapidly added dropwise. Thereaction mixture was then stirred at room temperature for 16 h. Thereaction mixture was concentrated in vacuo, and the resulting residuewas partitioned between water and ethyl acetate. The ethyl acetate phasewas then dried and concentrated in vacuo, leaving 2.2 g (82%) of theproduct.

b) N(2(R,S)-3(S)-3-Amino-4-phenylbutan-2-ol-1-yl)methanesulfonamide[sic]

1.85 g (5.1 mmol) of intermediate 3a were dissolved in 50 ml ofmethylene chloride, and 50 ml of saturated ethereal hydrogen chloridesolution were added. The mixture was stirred at room temperature for 1h. The reaction mixture was then concentrated in vacuo, and theresulting residue was treated with eher [sic], whereupon the productslowly separated out as hydrochloride. Yield 1.5 g (97%).

c)N(2(R,S)-3(S)-1-Methanesulfonamido-4-phenylbutan-2-ol-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)benzamide[sic]

0.6 g (2.0 mmol) of intermediates [sic] 3b and 0.46 g (2.1 mmol) ofintermediate 2b were reacted in analogy to method 1g, resulting in 0.62g (65%) of the product.

d)N(3(S)-1-Methanesulfonamido-4-phenylbutan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)benzamide[sic]

0.5 g of intermediate 3c were oxidized in analogy to method 1h,resulting in 0.35 g of the product.

¹H-NMR (D₆-DMSO): δ=2.7-3.0 (3H), 3.1-3.4 (2H), 4.1-4.4 (2H), 4.9 (1H),7.1-8.0 (13H), 8.5 (2H) and 9.0 (1H) ppm.

Example 4N(3(S)-1-Methanesulfonamido-4-phenylbutan-2-on-3-yl)-3(2-naphthylsulfonamido)benzamide[sic]

a)N(2(R,S)-3(S)-1-Methanesulfonamido-4-phenylbutan-2-ol-3-yl)-2(2-naphthylsulfonamido)benzamide[sic]

0.8 [lacuna] (2.0 mmol) of intermediates [sic] 3b and 0.86 g (2.1 mmol)of intermediate 1f were reacted in analogy to method 1g, resulting in1.2 g (81%) of the product.

d) [sic]N(3(S)-1-Methanesulfonamido-4-phenylbutan-2-on-3-yl)-2(2-naphthylsulfonamido)benzamide[sic]

1.1 g of intermediate 4a were oxidized in analogy to method 1h,resulting in 0.73 g of the product.

¹H-NMR (D₆-DMSO): δ=2.8-3.0 (3H), 3.1-3.3 (2H), 3.9-4.2 (2H), 4.8 (1H),7.0-8.2 (17H), 8.4 (1H), 8.8 (1H) and 10.8 (broad) ppm.

Example 5N(3(S)-1-Benzamido-4-phenylbutan)-2-on-3-yl)-(2-naphthylsulfonamido)benzamide[sic]

a) O(tert-Butyl)N(2(R,S)-3(S)-1-benzamidoamido-4-phenylbutan-2-ol-3-yl)carbamate [sic]

2.5 g (7.3 mmol) of intermediate 1b were dissolved in 25 ml of pyridine.Then, at 0° C., 1.1 g (7.7 mmol) of benzoyl chloride, dissolved in 5 mlof anhydrous tetrahydrofuran, were rapidly added dropwise. The reactionmixture was then stirred at room temperature for 16 h. The reactionmixture was diluted to 10 times the volume with an aqueous sodiumbicarbonate solution, whereupon the product crystallized out. 1.3 g(46%) of the product were obtained.

b) N(2(R,S)-3(S)-3-Amino-4-phenylbutan-2-ol-1-yl)benzamide [sic]

1.2 g (3.0 mmol) of intermediate 5a were dissolved in 50 ml of methylenechloride, and 20 ml of saturated ethereal hydrogen chloride solutionwere added. The mixture was stirred at room temperature for 1 h. Thereaction mixture was then concentrated in vacuo, and the resultingresidue was treated with eher [sic], whereupon the product slowlyseparated out as hydrochloride. Yield 1.0 g (99%).

c)N(3(S)-1-Benzamido-4-phenylbutan-2-on-3-yl)-2(2-naphthylsulfonamido)benzamide[sic]

0.52 [lacuna] (2.0 mmol) of intermediates [sic] 5b and 0.53 g (1.6 mmol)of intermediate 1f were reacted in analogy to method 1g, resulting in0.89 g (92%) of the product.

d)N(3(S)-1-Benzamido-4-phenylbutan-2-on-3-yl)-2(2-naphthylsulfonamido)benzamide[sic]

0.78 g of intermediate 5c were oxidized in analogy to method 1h,resulting in 0.72 g of the product.

¹H-NMR (D₆-DMSO): δ=2.8 (1H), 3.3 (1H), 4.3 (2H), 4.7 (1H), 7.0-8.3(20H), 8.4 (1H) and 8.7-8.9 (2H) ppm.

Example 6N(3(S)-4-Phenyl-1-benzamidobutan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)benzamide[sic]

a)N(2(R,S)-3(S)-4-Phenyl-1-benzamidobutan-2-ol-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)benzamide[sic]

0.4 [lacuna] (1.25 mmol) of intermediates [sic] 5b and 0.28 g (1.25mmol) of intermediate 2b were reacted in analogy to method 1g, resultingin 0.54 g (88%) of the product.

b)N(3(s)-4-Phenyl-1-benzamidobutan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)benzamide[sic]

0.48 g of intermediate 6a was oxidized in analogy to method 1h,resulting in 0.42 g of the product.

MS: m/e=489 (M⁺).

The following compounds were prepared in analogy to the above examples:

Example 73(4(1(N,N-Dimethylamino)-1-ethyl)-phenylsulfonamido)-N(1-phenylsulfonamido-heptan-2-on-3-yl)benzamide

¹H-NMR (CDCl₃): δ=0.7-1.0 (3H), 1.0-1.8 (12H), 2.9-3.2 (8H), 3.9-4.2(2H), 4.6 (1H), 7.2-8.0 (14H) ppm.

Example 8N(1-Phenylsulfonamido-heptan-2-on-3-yl)-3(4(1(piperinidin-1-yl)-1-ethylphenylsulfonamido)benzamide

¹H-NMR (D₆-DMSO): δ=0.8 (3H), 1.1-1.8 (10H), 3.1 (1H), 3.9 (2H), 4.4(1H), 7.2-8.1 (14H) and 8.7 (1H) ppm.

Example 93(4(1(4-Methylpiperazin-1-yl)-1-ethyl)phenylsulfonamido)-N(1-phenylsulfonamidoheptan-2-on-3-yl)benzamide

¹H-NMR (CDCl₃): δ=0.9 (6H), 1.1-1.6 (6H), 2.3-2.8 (11H), 3.1 (1H),3.9-4.1 (2H), 4.7 (1H) and 7.2-8.0 (14H) ppm.

The following examples can be prepared in analogy to the above examples:

N(3(S)-4-Phenyl-1-phenylsulfonamido-butan-2-on-3-yl)-2(E-2-phenyl-1-ethenyl)-benzamide

2(E-2(3,4-Dimethoxyphenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-phenylsulfonamido-butan-2-on-3-yl)benzamide

2(E-2(2-Naphthyl)-1-ethenyl)-N(3(S)-4-phenyl-1-phenylsulfonamidobutan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Dimethylaminomethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-phenylsulfonamido-butan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Diethylaminomethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-phenylsulfonamido-butan-2-on-3-yl)-benzamide

N(3(S)-4-Phenyl-1-phenylsulfonamido-butan-2-on-3-yl)-2(E-2(4-(pyrrolidin-1-ylmethyl)-phenyl)-1-ethenyl)-benzamide

2(E-2(4(Piperidin-1-ylmethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-phenylsulfonamido-butan-2-on-3-yl)-benzamide

2(E-2(4((4-Methylpiperazin-1-yl)methyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-phenylsulfon-amido-butan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Benzyl-methylaminomethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-phenylsulfon-amido-butan-2-on-3-yl)-benzamide

2(E-2(4(4-Ethylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-phenylsulfon-amido-butan-2-on-3-yl)-benzamide

2(E-2(4(4-Benzylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-phenylsulfon-amido-butan-2-on-3-yl)-benzamide

N(1-Phenylsulfonamido-heptan-2-on-3-yl)-2(E-2-phenyl-1-ethenyl)benzamide

2(E-2(3,4-Dimethoxyphenyl)-1-ethenyl)-N(-1-phenylsulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(2-Naphthyl)-1-ethenyl)-N(1-phenylsulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Dimethylaminomethyl)phenyl)-1-ethenyl)-N(1-phenylsulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Diethylaminomethyl)phenyl)-1-ethenyl)-N(1-phenylsulfonamido-heptan-2-on-3-yl)-benzamide

N(1-Phenylsulfonamido-heptan-2-on-3-yl)-2(E-2(4(pyrrolidin-1-ylmethyl)-phenyl)-1-ethenyl)-benzamide

2(E-2(4(Piperidin-1-ylmethyl)phenyl)-1-ethenyl)-N(1-phenylsulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(4((4-Methylpiperazin-1-yl)methyl)phenyl)-1-ethenyl)-N(1-phenylsulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Benzyl-methylaminomethyl)phenyl)-1-ethenyl)-N(-1-phenylsulfon-amido-heptan-2-on-3-yl)-benzamide

2(E-2(4(4-Ethylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-N(-1-phenylsulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(4(4-Benzylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-N(1-phenylsulfonamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Methansulfonamido-heptan-2-on-3-yl)-2(E-2-phenyl-1-ethenyl)-benzamide

2(E-2(3,4-Dimethoxyphenyl)-1-ethenyl)-N(3(S)-1-methansulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(2-Naphthyl)-1-ethenyl)-N(3(S)-1-methansulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Dimethylaminomethyl)phenyl)-1-ethenyl)-N(3(S)-1-methansulfonamido-hepan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Diethylaminomethyl)phenyl)-1-ethenyl)-N(3(S)-1-methansulfonamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Methansulfonamido-heptan-2-on-3-yl)-2(E-2(4(pyrrolidin-1-ylmethyl)-phenyl)-1-ethenyl)-benzamide

2(E-2(4(Piperidin-1-ylmethyl)phenyl)-1-ethenyl)-N(3(S)-1-methansulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(4((4-Methylpiperazin-1-yl)methyl)phenyl)-1-ethenyl)-N(3(S)-1-methansulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Benzyl-methylaminomethyl)phenyl)-1-ethenyl)-N(3(S)-1-methansulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(4(4-Ethylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-N(3(S)-1-methansulfonamido-heptan-2-on-3-yl)-benzamide

2(E-2(4(4-Benzylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-N(3(S)-1-methansulfonamido-heptan-2-on-3-yl)-benzamide

N(3(S)-4-Phenyl-1-methansulfonamido-butan-2-on-3-yl)-2(E-2-phenyl-1-ethenyl)-benzamide

2(E-2(3,4-Dimethoxyphenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-methansulfonamido-butan-2-on-3-yl)-benzamide

2(E-2(2-Naphthyl)-1-ethenyl)-N(3(S)-4-phenyl-1-methansulfonamido-butan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Dimethylaminomethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-methansulfonamido-butan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Diethylaminomethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-methansulfonamido-butan-2-on-3-yl)-benzamide

N(3(S)-4-Phenyl-1-methansulfonamido-butan-2-on-3-yl)-2(E-2(4-(pyrrolidin-1-ylmethyl)-phenyl)-1-ethenyl)-benzamide

2(E-2(4(Piperidin-1-ylmethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-methansulfonamido-butan-2-on-3-yl)-benzamide

2(E-2(4((4-Methylpiperazin-1-yl)methyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-methansulfon-amido-butan-2-on-3-yl)-benzamide

2(E-2(4(N,N-Benzyl-methylaminomethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-methansulfon-amido-butan-2-on-3-yl)-benzamide

2(E-2(4(4-Ethylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-methansulfon-amido-butan-2-on-3-yl)-benzamide

2(E-2(4(4-Benzylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-N(3(S)-4-phenyl-1-methansulfon-amido-butan-2-on-3-yl)-benzamide

N(3(S)-4-Phenyl-1-phenylsulfonamido-butan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Phenylsulfonamido-heptan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Methansulfonamido-heptan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)-benzamide

N(3(S)-Benzamido-heptan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)-benzamide

N(3(S)-Acetamido-heptan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Methansulfonamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Methansulfonamido-4-phenyl-butan-2-on-3-yl)-2(E-2(2-pyridyl)-1-ethenyl)-benzamide

N(3(S)-4-Phenyl-1-phenylsulfonamido-butan-2-on-3-yl)-2(E-2(2-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(2-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(2-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Phenylsulfonamido-heptan-2-on-3-yl)-2(E-2(2-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Methansulfonamido-heptan-2-on-3-yl)-2(E-2(2-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-heptan-2-on-3-yl)-2(E-2(2-pyridyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-heptan-2-on-3-yl)-2(E-2(2-pyridyl)-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2-phenyl-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2(3,4-dimethoxyphenyl)-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2(2-naphthyl)-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2(4(N,N-dimethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2(4(N,N-diethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2(4(pyrrolidin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2(4(piperidin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2(4((4-methylpiperazin-1-yl)methyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2(4(N,N-benzylmethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2(4(4-Ethylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-2(4(4-benzylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2-phenyl-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2(3,4-dimethoxyphenyl)-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2(2-naphthyl)-1-ethenyl)benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2(4(N,N-dimethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2(4(N,N-diethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2(4(pyrrolidin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2(4(piperidin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2(4((4-methylpiperazin-1-yl)methyl)phenyl)-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2(4(N,N-benzylmethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2(4(4-ethylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-2(4(4-benzylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2-phenyl-1-ethenyl)-benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2(3,4-dimethoxyphenyl)-1-ethenyl)-benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2(2-naphthyl)-1-ethenyl)benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2(4(N,N-dimethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2(4(N,N-diethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2(4(pyrrolidin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2(4(piperidin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2(4((4-methylpiperazin-1-yl)methyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2(4(N,N-benzylmethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2(4(4-ethylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(1-Benzamido-hexan-2-on-3-yl)-2(E-2(4(4-benzylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2-phenyl-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-heptan-2-on-3-yl)-2(E-2(3,4-dimethoxyphenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(2-naphthyl)-1-ethenyl)-benzamide

N((3S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(N,N-di-methylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(N,N-di-ethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(pyrrolidin-1-ylmethyl)-phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(piperidin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4((4-methylpiperazin-1-yl)methyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(N,N-benzylmethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(4-ethylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(4-benzylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2-phenyl-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-heptan-2-on-3-yl)-2(E-2(3,4-dimethoxyphenyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(2-naphthyl)-1-ethenyl)-benzamide

N((3S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(N,N-di-methylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(N,N-di-ethylaminomethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(pyrrolidin-1-ylmethyl)-phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(piperidin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4((4-methylpiperazin-1-yl)methyl)-phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(N,N-benzylmethylaminomethyl)-phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(4-ethylpiperazin-1-ylmethyl)phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-2(4(4-benzylpiperazin-1-ylmethyl)-phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylmethoxy)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-4(naphth-2-ylmethoxy)-benzamide

N(3(S)-1-Methansulfonylamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylmethoxy)-benzamide

N(1-Methansulfonylamido-heptan-2-on-3-yl)-4(naphth-2-ylmethoxy)benzamide

4(Naphth-2-ylmethoxy)-N(3(S)-1-phenylsulfonylamido-4-phenylbutan-2-on-3-yl)-benzamide

4(Naphth-2-ylmethoxy)-N(1-phenylsulfonylamido-heptan-2-on-3-yl)benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylmethoxy)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-4(naphth-2-ylmethoxy)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylmethylmercapto)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-4(naphth-2-ylmethylmercapto)benzamide

N(3(S)-1-Methansulfonylamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylmethylmercapto)-benzamide

N(1-Methansulfonylamido-heptan-2-on-3-yl)-4(naphth-2-ylmethylmercapto)-benzamide

4(Naphth-2-ylmethylmercapto)-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

4(Naphth-2-ylmethylmercapto)-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylmethylmercapto)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-4(naphth-2-ylmethylmercapto)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2-phenoxy-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2-phenoxy-benzamide

N(3(S)-1-Methansulfonylamido-4-phenyl-butan-2-on-3-yl)-2-phenoxybenzamide

N(1-Methansulfonylamido-heptan-2-on-3-yl)-2-phenoxy-benzamide

2-Phenoxy-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)benzamide

2-Phenoxy-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2-phenoxy-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2-phenoxy-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylamido)benzamide

N(1-Acetamido-heptan-2-on-3-yl)-4(naphth-2-ylamido)-benzamide

N(3(S)-1-Methansulfonylamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylamido)-benzamide

N(1-Methansulfonylamido-heptan-2-on-3-yl)-4(naphth-2-ylamido)-benzamide

4(Naphth-2-ylamido)-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

4(Naphth-2-ylamido)-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylamido)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-4(naphth-2-ylamido)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylsulfonamido)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-4(naphth-2-ylsulfonamido)-benzamide

N(3(S)-1-Methansulfonylamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylsulfonamido)-benzamide

N(1-Methansulfonylamido-heptan-2-on-3-yl)-4(naphth-2-ylsulfonamido)-benzamide

4(Naphth-2-ylsulfonamido)-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

4(Naphth-2-ylsulfonamido)-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-4(naphth-2-ylsulfonamido)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-4(naphth-2-ylsulfonamido)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-3(naphth-2-ylsulfonamido)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-3(naphth-2-ylsulfonamido)-benzamide

N(1-Methansulfonylamido-heptan-2-on-3-yl)-3(naphth-2-ylsulfonamido)-benzamide

3(Naphth-2-ylsulfonamido)-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-3(naphth-2-ylsulfonamido)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-3-phenylsulfonamidobenzamide

N(1-Acetamido-heptan-2-on-3-yl)-3-phenylsulfonamido-benzamide

N(3(S)-1-Methansulfonylamido-4-phenyl-butan-2-on-3-yl)-4-phenylsulfonamido-benzamide

N(1-Methansulfonylamido-heptan-2-on-3-yl)-3-phenylsulfonamido-benzamide

3-Phenylsulfonamido-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

3-Phenylsulfonamido-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-3-phenylsulfonamido-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-3-phenylsulfonamido-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2-phenyl-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2-phenyl-benzamide

N(3(S)-1-Methansulfonylamido-4-phenyl-butan-2-on-3-yl)-2-phenyl-benzamide

N(1-Methansulfonylamido-heptan-2-on-3-yl)-2-phenyl-benzamide

2-Phenyl-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

2-Phenyl-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2-phenyl-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2-phenyl-benzamide

2-(4(N,N-Dimethylaminomethyl)-phenyl)-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

2-(4(N,N-Diethylaminomethyl)-phenyl)-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

N(3(S)-1-Phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-2-(4-pyrrolidin-1-ylmethyl)-phenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-3(chinolin-8-ylsulfonamido)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-3(chinolin-8-ylsulfonamido)-benzamide

3(Chinolin-8-ylsulfonamido)-N(3(S)-1-methansulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

3(Chinolin-8-ylsulfonamido)-N(1-methansulfonylamido-heptan-2-on-3-yl)-benzamide

3(Chinolin-8-yllsulfonamido)-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

3(Chinolin-8-ylsulfonamido)-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-3(chinolin-8-ylsulfonamido)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-3-phenylsulfonamido-benzamide

2-(4-(N,N-Dimethylaminomethyl)phenoxy-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

2-(4-(N,N-Dimethylaminomethyl)phenoxy-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

2-(4-(N,N-Diethylaminomethyl)phenoxy-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

2-(4-(N,N-Diethylaminomethyl)phenoxy-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-2(4-pyrrolidin-1-ylmethyl)phenoxy-benzamide

N(1-phenylsulfonylamido-heptan-2-on-3-yl)-2-(4-pyrroidin-1-yl)phenoxy-benzamide

N(4-Cyclohexyl-1-phenylsulfonamido-butan-2-on-3-yl)-2(E-2(4(N,N-dimethylaminomethyl)-phenyl)-1-ethenyl)-benzamide

N(4-Cyclohexyl-1-phenylsulfonamido-butan-2-on-3-yl)-2(E-2(4(N,N-diethylaminomethyl)-phenyl)-1-ethenyl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-2(E-naphtho-2-yl-1-ethenyl)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-2(E-naphtho-2-yl-1-ethenyl)-benzamide

N(3(S)-1-Methansulfonylamido-4-phenyl-butan-2-on-3-yl)-2(E-naphtho-2-yl-1-ethenyl)-benzamide

N(1-Methansulfonylamido-heptan-2-on-3-yl)-2(E-naphtho-2-yl-1-ethenyl)-benzamide

2(E-Naphtho-2-yl-1-ethenyl)-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

2(E-Naphtho-2-yl-1-ethenyl)-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-2(E-naphtho-2-yl-1-ethenyl)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-2(E-naphtho-2-yl-1-ethenyl)-benzamide

2(E-2-Benzoyl-1-ethenyl)-N(3(S)-1-phenylsulfonylamido-4-phenylbutan-2-on-3-yl)-benzamide

N(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-6-methyl-4(naphth-2-ylamido)-benzamide

N(1-Acetamido-heptan-2-on-3-yl)-6-methyl-4(naphth-2-ylamido)-benzamide

N(3(S)-1-Methansulfonylamido-4-phenyl-butan-2-on-3-yl)-6-methyl-4(naphth-2-ylamido)-benzamide

N(1-Methansulfonylamido-heptan-2-on-3-yl)-6-methyl-4(naphth-2-ylamido)-benzamide

6-Methyl-4(naphth-2-ylamido)-N(3(S)-1-phenylsulfonylamido-4-phenyl-butan-2-on-3-yl)-benzamide

6-Methyl-4(naphth-2-ylamido)-N(1-phenylsulfonylamido-heptan-2-on-3-yl)-benzamide

N(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-6-methyl-4(naphth-2-ylamido)-benzamide

N(1-Benzamido-heptan-2-on-3-yl)-6-methyl-4(naphth-2-ylamido)-benzamide

3(N(3(S)-4-Phenyl-1-phenylsulfonamido-butan-2-on-3-yl)-4-carbamoyl-phenyl)-naphtho[c]pyrimidione

3(N-(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-4-carbamoylphenyl)-naphtho[c]pyrimidione

3(N-(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-4-carbamoylphenyl)-naphtho[c]pyrimidione

3(N(3(S)-1-Methansulfonamido-4-phenyl-butan-2-on-3-yl)-4-carbamoylphenyl)-naphtho[c]pyrimidione

3(N(1-Phenylsulfonamido-heptan-2-on-3-yl)-4-carbamoylphenyl)-naphtho[c]pyrimidione

3(N-(1-Benzamido-heptan-2-on-3-yl)-4-carbamoylphenyl)-naphtho[c]pyrimidione

3(N-(1-Acetamido-4-phenyl-heptan-2-on-3-yl)-4-carbamoylphenyl)-naphtho[c]pyrimidione

3(N(1-Methansulfonamido-heptan-2-on-3-yl)-4-carbamoylphenyl)-naphtho[c]pyrimidione

2(N(3(S)-4-Phenyl-1-phenylsulfonamido-butan-2-on-3-yl)-4-carbamoylphenyl)-benzo[c]phthalimide

2(N-(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-4-carbamoylphenyl)-benzo[c]phthalimide

2(N-(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-4-carbamoylphenyl)-benzo[c]phthalimide

2(N(3(S)-1-Methansulfonamido-4-phenyl-butan-2-on-3-yl)-4-carbamoylphenyl)-benzo[c]phthalimide

2(N(1-Phenylsulfonamido-heptan-2-on-3-yl)-4-carbamoylphenyl)benzo[c]phthalimide

2(N-(1-Benzamido-heptan-2-on-3-yl)-4-carbamoylphenyl)benzo[c]phthalimide

2(N-(1-Acetamido-4-phenyl-heptan-2-on-3-yl)-4-carbamoylphenyl)-benzo[c]phthalimide

2(N(1-Methansulfonamido-heptan-2-on-3-yl)-4-carbamoylphenyl)-benzo[c]phthalimide

2(N(3(S)-4-Phenyl-1-phenylsulfonamido-butan-2-on-3-yl)-3-carbamoyl-6-methyl-phenyl)-benzo[c]phthalimide

2(N-(3(S)-1-Benzamido-4-phenyl-butan-2-on-3-yl)-3-carbamoyl-6-methyl-phenyl)-benzo[c]phthalimide

2(N-(3(S)-1-Acetamido-4-phenyl-butan-2-on-3-yl)-3-carbamoyl-6-methyl-phenyl)-benzo[c]phthalimide

2(N(3(S)-1-Methansulfonamido-4-phenyl-butan-2-on-3-yl)-3-carbamoyl-6-methyl-phenyl)-benzo[c]phthalimide

2(N(1-Phenylsulfonamido-heptan-2-on-3-yl)-3-carbamoyl-6-methyl-phenyl)-benzo[c]phthalimide

2(N-(1-Benzamido-heptan-2-on-3-yl)-3-carbamoyl-methyl-phenyl)-benzo[c]phthalimide

2(N-(1-Acetamido-4-phenyl-heptan-2-on-3-yl)-3-carbamoyl-6-methyl-phenyl)-benzo[c]phthalimide

2(N(1-Methansulfonamido-heptan-2-on-3-yl)-3-carbamoyl-6-methyl-phenyl)-benzo[c]phthalimide

We claim:
 1. A benzamide of formula I

or a tautomeric form, an enantiomeric or diastereomeric form, an E or Zform, or a physiologically tolerated salt thereof, wherein R¹ isC₁-C₆-alkyl, where one of the C atoms is optionally substituted by aphenyl ring, a cyclohexyl ring, an indolyl ring or an SCH₃ group, andthe phenyl ring in turn is unsubstituted or substituted by one or two R⁴radicals, R² is NR⁵CO—R⁶ or NHR⁵SO₂—R⁶, R³ is chlorine, bromine,fluorine, C₁-C₆-alkyl, NHCO—C₁-C₄-alkyl, NHSO₂—C₁-C₄-alkyl, NO₂,—O—C₁-C₄-alkyl, CN, COOH, CONH₂, COO—C₁-C₄-alkyl, SO₂—C₁-C₄-alkyl,—SO₂Ph, SO₂NH—C₁-C₄-alkyl, iodine, SO₂NH₂ or NH₂, A is an aromatic ringor a heteroaromatic ring selected from the group consisting of naphthyl,quinolyl, quinoxyl, benzimidazolyl, benzothienyl, quinazolyl, phenyl,thienyl, imidazolyl, pyridyl, pyrimidyl and pyridazyl, which ring isoptionally substituted by R⁹ and up to 2 R⁸ radicals, B is a bond,—(CH₂)_(m)—, —(CH₂)_(m)—O—(CH₂)_(o)—, —(CH₂)_(o)—S—(CH₂)_(m)—,—(CH₂)_(o)—SO—(CH₂)_(m)—, —(CH₂)_(o)—SO₂—(CH₂)_(m)—, —CH═CH—, —C≡C—,—CO—CH═CH—, —(CH₂)_(o)—CO—(CH₂)_(m)—, —(CH₂)_(m)—NHCO—(CH₂)_(o)—,—(CH₂)_(m)—CONH—(CH₂)_(o)—, —(CH₂)_(m)—NHSO₂—(CH₂)_(o)—, —NH—CO—CH═CH—,—(CH₂)_(m)—SO₂NH—(CH₂)_(o)—, or A—B represents a radical of formula

R⁴ is hydrogen, C₁-C₄-alkyl, —O—C₁-C₄-alkyl, OH, Cl, F, Br, I, CF₃, NO₂,NH₂, CN, COOH, COO—C₁-C₄-alkyl or NHCO—C₁-C₄-alkyl, R⁵ is hydrogen orC₁-C₄-alkyl, R⁶ is hydrogen, phenyl, naphthyl, C₁-C₆-alkyl, where one ofthe C atoms is optionally substituted by a phenyl ring which in turn isunsubstituted or substituted by one or two R⁴ radicals, R⁸ is hydrogen,C₁-C₄-alkyl, —O—C₁-C₄-alkyl, OH, Cl, F, Br, I, CF₃, NO₂, NH₂, CN, COOH,COO—C₁-C₄-alkyl, —NHCO—C₁-C₄-alkyl, phenyl, NHCO-phenyl,—NHSO₂—C₁-C₄-alkyl, —NHSO₂-phenyl, —SO₂—C₁-C₄-alkyl, pyridyl orSO₂-phenyl, R⁹ is hydrogen, —NHR¹⁰R¹³,

 or —CHR¹⁴—(CH₂)_(p)—R¹², R¹⁰ is C₁-C₆-alkyl which optionally carries aphenyl ring which is in turn substituted by a maximum of two R¹¹radicals, R¹¹ is hydrogen, C₁-C₄-alkyl, —O—C₁-C₄-alkyl, OH, Cl, F, Br,I, CF₃, NO₂, NH₂, CN, COOH, COO—C₁-C₄-alkyl, NHCO—C₁-C₄-alkyl,—NHSO₂—C₁-C₄-alkyl or —SO₂—C₁-C₄-alkyl; R¹² is pyrrolidinyl,morpholinyl, piperidinyl, hexahydroazepinyl or homopiperazinyl, R¹³ ishydrogen or C₁-C₆-alkyl, n, p are, independently of one another, 0, 1 or2, and m, o are, independently of one another, 0, 1, 2, 3 or
 4. 2. Thebenzamide of formula I defined in claim 1, where A is phenyl ornaphthyl, each of which is unsubstituted or substituted by R⁹, B is—SO₂NH—, —CH═CH—, a bond, or —C≡C—, R¹ is ethyl, propyl, butyl orbenzyl, R² is NH—SO₂—R⁶ R³ is hydrogen or COOH, R⁶ is C₁-C₄-alkyl orphenyl, R⁹ is hydrogen, —NHR¹⁰R¹³,

 or —CHR¹⁴—R¹², R¹⁰ is C₁-C₆-alkyl, R¹² is pyrrolidinyl, morpholinyl orpiperidinyl, R¹³ is C₁-C₄-alkyl, and R¹⁴ is hydrogen, methyl or ethyl.3. The benzamide of formula I defined in claim 1, where A is phenyl ornaphthyl, each of which is unsubstituted or substituted by R⁹, B is—SO₂NH—, —CH═CH—, a bond, or —C≡C—, R¹ is ethyl, propyl, butyl orbenzyl, R² is NH—CO—R⁶, R³ is hydrogen or COOH, R⁶ is C₁-C₄-alkyl orphenyl, R⁹ is hydrogen, —NHR¹⁰R¹³,

 or —CHR¹⁴—R¹², where R¹⁰ is C₁-C₆-alkyl, R¹² is pyrrolidinyl,morpholinyl or piperidinyl, R¹³ is C₁-C₄-alkyl, and R¹⁴ is hydrogen,methyl or ethyl.
 4. The benzamide of formula I defined in claim 1, whereA is phenyl which is optionally substituted by R⁹, B is —CH═CH—, and Band the moiety

 are bonded to adjacent C atoms of the phenyl ring in formula I, R¹ isbutyl or benzyl, R² is NH—SO₂—R⁶, R³ is hydrogen, R⁶ is C₁-C₄-alkyl orphenyl, R⁹ is hydrogen, —NHR¹⁰R¹³,

 or —(CH₂)—R¹², R¹⁰ is C₁-C₆-alkyl, R¹² is pyrrolidinyl, morpholinyl orpiperidinyl, and R¹³ is C₁-C₄-alkyl.
 5. A method of using the benzamideof formula I defined in claim 1 for producing a pharmaceuticalcomposition which is adapted for reducing an elevated level of acysteine protease in a patient, which method comprises admixing atherapeutically effective amount of the benzamide with customarypharmaceutical auxiliaries.
 6. A pharmaceutical composition, comprisingconventional pharmaceutical ancillary substances a therapeuticallyeffective amount of at least one benzamide of formula I as defined inclaim 1.